We are using the tools of oncogenetics and viral genetics to study the molecular events that might be responsible for the well- established relationship between chronic infection with hepatitis B viruses and the appearance of primary hepatocellular carcinoma. In this application to continue an established program, we emphasize two general approaches: (1) The behavior of wild-type and recombinant rodent hepatitis B viruses is being examined in two natural hosts for such viruses, the Eastern woodchuck and Beechey ground squirrel, to identify viral and host determinants of host range and pathogenicity. (2) A collection of PHCs from patients in Hong Kong is being analyzed for rearrangements and aberrant expression of known cellular proto-oncogenes and for insertional activation of chromosomal domains that might harbor previously unknown proto-oncogenes by hepatitis virus DNA.